CN103476743B - Mixed crystal agomelatine (Form-VIII), preparation method and use thereof and pharmaceutical composition containing same - Google Patents

Abstract

The present invention provides a mixed crystal agomelatine (Form-VIII), the preparation method and use thereof and a pharmaceutical composition containing the same, wherein the mixed crystal mainly contains an agomelatine crystal form VI. The mixed crystal is stable and has good reproducibility, and is found through a stability test to be superior to a crystal form VI in terms of stability. Therefore, the Form-VIII of the present invention has an advantage in terms of preparation.

Description

Mixed crystal of agomelatine (Form-VIII), its preparation method, application and pharmaceutical composition containing it

technical field

The invention relates to a mixed crystal of agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, its preparation method, application and pharmaceutical composition containing it.

Background technique

Agomelatine (agomelatine), the chemical name is N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, the trade name is Valdoxan, and the chemical structure is as follows:

It has a dual action, not only as an agonist of receptors of the melatoninergic system, but also as an antagonist of 5HT _2C receptors, and its properties make it active in the central nervous system, especially in major depression, seasonal affective disorder, It is active in the treatment of sleep disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue caused by jet lag, appetite disorders and obesity. It is the first melatonin-type antidepressant that is effective in the treatment of depression, improves sleep parameters and does not affect sexual function.

Agomelatine, its preparation and its therapeutic use have been reported in European patent specification EP0447285.

Given the pharmaceutical value of this compound, it is important to obtain this compound in a pure, stable, and reproducible crystalline form, giving it advantages in formulation and being stable enough for long-term storage with no effect on temperature, light, humidity, or oxygen levels. There are no specific requirements.

There have been many literature reports on agomelatine, such as patents CN200510071611.6, CN200610108396.7, CN200610108394.8, CN200610108395.2, CN200910047329.2, CN200910245029.5, etc. Crystal forms and methods for their preparation.

Among them, the crystal form VI disclosed in the CN200910047329.2 patent is obtained by recrystallization from acetic acid and water, which is superior to most of the currently disclosed crystal forms in terms of solubility, so it has unique value in preparations, but the crystal form VI can be used under extremely harsh conditions ( High temperature (60°C) for 10 days, a small amount of crystal transformation will occur. In order to find out crystal forms or mixed crystals with better stability without reducing solubility, it has become another focus of researchers.

It is gratifying that, through exploration of the preparation process and stability comparison, the inventors have found a mixed crystal whose stability is better than that of the crystal form VI under severe conditions. The mixed crystal not only does not reduce the excellent solubility of the crystal form VI, but also has better stability, and the preparation method is reproducible, and the prepared preparations have good stability under harsh conditions, thus greatly increasing the possibility of making it into a drug.

Contents of the invention

The object of the present invention is to provide a mixed crystal (Form-VIII) of agomelatine, and provide a preparation method thereof, and the Form-VIII is more stable under high temperature conditions than the VI crystal form, and in terms of preparation exhibits valuable properties.

The mixed crystal of agomelatine (form-Ⅷ) of the present invention can be used to treat melatoninergic system diseases, sleep disorders, tension, anxiety, seasonal affective disorder, severe depression, cardiovascular diseases, digestive system diseases , insomnia or fatigue from jet lag, schizophrenia, phobias or depression.

Another object of the present invention is to provide a preparation method of agomelatine Form-VIII, which has simple operation and good reproducibility.

Another object of the present invention is to provide a pharmaceutical composition, which comprises the mixed crystal (Form-VIII) of agomelatine of the present invention and pharmaceutically acceptable adjuvants or excipients.

The pharmaceutical compositions can be formulated for various routes of administration, especially for oral administration or injection.

The administered dose can be adjusted according to the nature and severity of the disease, the route of administration, and the age and weight of the patient. The dosage varies from 0.1 mg to 1 g per day, and can be administered once or divided into several times.

Form-VIII of agomelatine of the present invention is characterized by the following X-ray diffraction pattern expressed in interplanar distance d, Bragg 2θ angle and relative intensity (1%):

When measuring the crystals of the present invention by X-ray diffraction, sometimes there is a slight measurement error for the measured peak due to the measurement instrument or measurement conditions. Specifically, for example, the measurement error of the 2θ value is sometimes about ±0.2 , even when using very precise equipment, there is sometimes an error of about ±0.1. Therefore, this error should be taken into account when determining each crystal structure.

The XRD test condition of the form-VIII of agomelatine of the present invention:

Instrument model: Bruker D8ADVANCE X-ray diffractometer

Experimental parameters:

Detector: LynxEye detector

Light source: CuKα40kV40mA

Monochromator: Ni filter

Divergence slit: 1°

DivH.L.Slit: 1.0mm

Detector: LynxEye detector

Scanning mode: θ-θ continuous scanning

Scanning range: 3°～45°

Step size: 0.02°

Scanning speed: 8.0°/min

Scanning time: 5min

Scanning temperature: room temperature

The test condition of the DSC endothermic transition spectrum of the form-VIII of agomelatine of the present invention is: instrument model: NETZSCH DSC204F1

Experimental conditions:

Crucible type: aluminum crucible (needle pierced)

Protective gas: high-purity nitrogen, 20ml/min

Sweeping gas: high-purity nitrogen, 60ml/min

Heating rate: 10°C/min

Temperature range: room temperature to 140°C

The DSC endothermic transition in the present invention is characterized by the onset value of the main endothermic peak in the spectrum, the onset value ranges from 97-98°C, and the area of the main endothermic peak is not less than 90%, preferably 95-99%. .

When measuring the crystals of the present invention by DSC, sometimes there is a slight measurement error for the measured peak due to the instrument used for the measurement or the conditions of the measurement. Specifically, for example, the measurement error of the onset value is sometimes about ±1°C, Even when using very precise equipment, an error of about ±0.5°C may sometimes occur. Therefore, this error should be taken into account when determining each crystal structure.

In the present invention, TGA test condition is:

Instrument model NETZSCH TG209F1

Experimental conditions

Crucible type: Al ₂ O ₃

Sweeping gas: N ₂ 20ml/min; protective gas: N ₂ 10ml/min

Temperature range: room temperature to 300°C

Heating rate: 10°C/min

The preparation method of the form-VIII of the present invention, the method is to dissolve the agomelatine complex (Agomelatine-HCl-H ₂ O) of the formula II in acetic acid, and then add sodium acetate thereinto, by adding to the obtained reaction Add water dropwise to the liquid and stir at 7-13°C to precipitate crystals, and then separate the crystals from the liquid phase.

The amount of acetic acid in the present invention has no special requirement, it is based on the ability to dissolve raw materials, and it can be properly heated to aid in dissolution according to requirements.

The molar ratio of agomelatine complex of formula II to sodium acetate is preferably 1:1-1.5, particularly preferably 1:1-1.1.

In the preparation method of the present invention, the volume ratio of acetic acid to water is 1:15-30.

In a preferred embodiment of the preparation method of form-VIII of agomelatine of the present invention, when the obtained reaction solution is at 12-18°C, especially at about 15°C, crystallization is carried out by adding water dropwise thereto Precipitate.

In another preferred embodiment, crystals are precipitated by adding water dropwise to the obtained reaction solution and stirring at about 10° C., for example, for 1.5 hours.

In another preferred embodiment, after adding sodium acetate, the reaction solution is heated to 40-80°C, optionally, an appropriate amount of activated carbon is added to it and stirred, and then filtered; then the solution is naturally cooled, and the Water was added dropwise to precipitate crystals.

The form-VIII of agomelatine provided by the present invention can be prepared into various pharmaceutical dosage forms together with various pharmaceutical auxiliary materials or excipients.

The present invention obtains a form-VIII of agomelatine, which is more stable than the VI crystal form and has the advantage of good stability in preparation.

According to the Chinese patent application CN201010126254.X, the agomelatine compound of the above formula II can be prepared by the following preparation method. The method is to react agomelatine with various forms of HCl to form a hydrate. There are two specific steps: first dissolve agomelatine in a water-containing organic solvent, then inject HCl gas, and then wash and dry the crystallized solid; or add agomelatine to a solvent containing HCl, Then the crystallized solid was washed and dried. If the first method is used to feed too much HCl, the yield will be reduced, and the second method is easy to control the amount of HCl in the solvent, so the second method is preferred.

Wherein, agomelatine can also be added to the aqueous organic solvent, and then the solvent containing HCl is added dropwise, and then the crystallized solid is washed and dried.

Similarly, agomelatine can also be added to an organic solvent, then an aqueous HCl solution is added dropwise, and then the crystallized solid is washed and dried.

The entire contents of cited or mentioned references are incorporated into this application by reference.

Description of drawings

Fig. 1 is the X-ray diffraction pattern of the Form-VIII obtained in Example 1 of the present invention;

Fig. 2 is the DSC endothermic transition spectrum of Form-VIII obtained in Example 1 of the present invention;

Fig. 3 is the X-ray diffraction pattern of the Form-VIII obtained in Example 2 of the present invention;

Fig. 4 is the DSC endothermic transition spectrum of form-VIII obtained in Example 2 of the present invention;

Fig. 5 is the X-ray diffraction pattern of Form-VIII obtained in Example 3 of the present invention;

Fig. 6 is the DSC endothermic transition spectrum of Form-VIII obtained in Example 3 of the present invention;

Fig. 7 is a TGA curve diagram of the thermogravimetric analysis of the product of Example 5 of the present invention.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples.

Embodiment 1 :

Dissolve the formula II agomelatine complex (14g) in acetic acid (55ml) solution, add sodium acetate (4.5g); heat to 60°C, add activated carbon (0.5g), stir for 2 hours, filter; when the filtrate When the temperature reached 15°C, water (1 L) was added dropwise, and the solution gradually became turbid, while stirring at ~10°C for 1.5 hours; filtered, washed the filter cake with water, and vacuum-dried at 45°C to constant weight to obtain 9.6 g of white solid;

(X-ray diffraction pattern is shown in Figure 1; DSC endothermic transition pattern is shown in Figure 2)

Embodiment 2 :

Dissolve the formula II agomelatine complex (140g) in acetic acid (490ml) solution, add sodium acetate (60g); heat to 60°C, add activated carbon (1.4g), stir for 1 hour, filter; when the filtrate reaches At 15°C, start to add water (8.8L) dropwise, and the solution gradually becomes turbid, while stirring at ~10°C for 1.5 hours; filter, wash the filter cake with water, and vacuum-dry at 45°C to constant weight to obtain 94g of white solid;

(X-ray diffraction pattern is shown in Figure 3; DSC endothermic transition pattern is shown in Figure 4)

Embodiment 3 :

Dissolve the formula II agomelatine complex (66g) in acetic acid (230ml) solution, add sodium acetate (21g); heat to 60°C, add activated carbon (1.3g), stir for 1 hour, filter; when the filtrate reaches When the temperature reached 15°C, water (6.9 L) was added dropwise, and the solution gradually became turbid, while stirring at ~10°C for 1.5 hours; filtered, washed the filter cake with water, and vacuum-dried at 50°C to constant weight to obtain 49 g of white solid;

(X-ray diffraction pattern is shown in Figure 5; DSC endothermic transition pattern is shown in Figure 6)

Embodiment 4 :

The crystal form VI and form-VIII of agomelatine (obtained from Example 2) were placed in a thermostat at 40° C. for 20 days, and the stability of these samples was studied by high performance liquid chromatography.

1. Determination of sample purity

Chromatographic conditions: use octadecylsilane bonded silica gel as a filler; use a mixed solution of 10mmol/L phosphate buffered saline (adjust the pH to 7.0 with sodium hydroxide) and acetonitrile with a volume ratio of 2:7 as the mobile phase; column temperature It is 40°C; the detection wavelength is 220nm. Purity was determined by internal standard method.

Form VI and Form-VIII were formulated into 1 mg/mL solutions with the mobile phase, and 10 μL of each was injected into the liquid chromatograph, and the chromatograms were recorded.

2. Determination of sample content

The determination method refers to the method for the determination of sample purity, and is determined by the external standard method, and the results are shown in Table 1:

Table I

3. Determination of water solubility

The determination method adopts the HPLC method, and the external standard method is used for determination. The results are as follows in Table 2:

Table II

sample name Form VI Form-Ⅷ Solubility (mg/ml) 0.336 0.335

4. Determination of crystal stability

The determination method adopts the stability assessment method in the Pharmacopoeia:

1) Influencing factor experiment (exposure for 10 days): high temperature (60°C), light (4500lx), high humidity (92.5%RH, 25°C)

2) Accelerated experiment (sealed for 6 months): temperature is 30°C, humidity is 65%RH

3) Long-term experiment (closed for 12 months): temperature is 25°C, humidity is 60%RH

Table three

According to the test results, it can be seen that the form-VIII of agomelatine of the present invention is more stable than the crystal form VI under high temperature conditions, and the solubility is also equivalent to the crystal form VI; the reproducibility of the preparation method is good, Displays valuable properties in terms of formulation.

5. Preparation and stability study of pharmaceutical composition (crystal form, purity and content)

According to the pharmacopoeia stability assessment research method, after the experiment of influencing factors (exposure for 10 days): high temperature (60°C), light (4500lx), high humidity (92.5%RH, 25°C); accelerated test (sealed for 6 months): The temperature is 30°C and the humidity is 65%RH; long-term experiment (closed for 12 months): the temperature is 25°C and the humidity is 60%RH. The assessment results show that the crystal form, purity and content of this product have not occurred under the above conditions. Change.

Therefore, the various test results of the bulk drug and capsules of this product show that form-Ⅷ has a good prospect of being a drug.

Embodiment 5: Formula II agomelatine complex

Add 10 g of agomelatine to 100 ml of ethyl acetate solution, add 4.6 g of HCl (36%) aqueous solution dropwise at 10°C, and stir for 1 hour; filter, wash the solid twice with 10 ml of ethyl acetate, 40 Dry at ℃ to obtain 10.2 g of white solid of formula II; purity: 99.8%, yield: 88.7%.

Cl elemental analysis:

Theoretical calculation value: Cl content is 11.91wt%

Measured value: Cl content is 11.86wt%

Determination of crystal water content of formula II agomelatine complex:

According to calculation, the theoretical content of crystallization water in C ₁₅ H ₁₇ NO ₂ ·HCl·H ₂ O is 6.06wt%.

5.1 Fisher's method (Appendix VIII M of "Chinese Pharmacopoeia" 2010 edition)

The product of Example 5 is tested according to the Fischer method, and the measured crystal water content: 6.15wt%

5.2 Thermogravimetric analysis (Appendix VIII Q of "Chinese Pharmacopoeia" 2010 Edition)

The product of Example 5 was tested according to the thermal analysis method, and the loss of crystal water was 6.67wt%, that is, the original product contained 6.67wt% of crystal water. Please refer to Figure 7 for the TGA curve.

Claims (16)

1. A mixed crystal of agomelatine, which is characterized by the following X-ray diffraction pattern represented by the Bragg 2θ angle: 2θ° 9.493 9.809 10.815 11.171 11.879 12.770 13.811 14.939 15.315 16.085 17.544 18.491 19.065 19.538 19.774 20.801 21.156 21.807 22.499 23.032 23.780 24.610 25.419 27.075 31.931 And it also includes crystals whose peak diffraction angles are matched within the above error of 2θ±0.2°. 2. A mixed crystal of agomelatine, which is characterized by the following X-ray diffraction pattern represented by interplanar distance d, Bragg 2θ angle and relative intensity: And it also includes crystals whose peak diffraction angles are matched within the above error of 2θ±0.2°. 3. The mixed crystal of agomelatine according to claim 1 or 2, characterized in that: in its DSC endothermic transition spectrum, the onset value is in the range of 97-98°C, and the main peak area ratio is not less than 90%. 4. the preparation method of the mixed crystal of agomelatine as described in any one in claim 1-3, formula Ⅱ agomelatine compound is dissolved in acetic acid, then adds sodium acetate wherein, by adding Add water dropwise to the obtained reaction solution and stir at 7-18°C to precipitate crystals, and then separate the crystals from the liquid phase 5. The preparation method according to claim 4, wherein the molar ratio of the agomelatine complex of formula II to sodium acetate is 1:1-1.5. 6. the preparation method as claimed in claim 4 or 5, wherein, the volume ratio of acetic acid and water is 1:15-30. 7. The preparation method according to any one of claims 4-6, wherein, when the obtained reaction liquid is at 12-18° C., crystals are precipitated by adding water therein dropwise. 8 . The production method according to claim 4 , wherein water is added dropwise to the obtained reaction liquid and stirred at 10° C. to precipitate crystals. 9. The preparation method according to any one of claims 4-8, wherein, after adding sodium acetate, the reaction solution is heated to 40-80°C; then the solution is allowed to cool naturally, and crystals are precipitated by adding water dropwise thereto . 10. A pharmaceutical composition comprising the mixed crystal of agomelatine according to any one of claims 1-3 and pharmaceutically acceptable excipients. 11. The pharmaceutical composition as claimed in claim 10 for preparing a medicament for treating diseases of the melatoninergic system. 12. the pharmaceutical composition as claimed in claim 10 for preparing medicine, described medicine is used for the treatment of sleep disorder, tension, anxiety disorder, seasonal affective disorder, cardiovascular disease, digestive system disease, schizophrenia, fear disease or depression. 13. The pharmaceutical composition as claimed in claim 10 for preparing a medicament for treating severe depression or insomnia or fatigue caused by jet lag. 14. The use of the mixed crystal of agomelatine according to any one of claims 1-3 in the preparation of medicines for treating diseases of the melatoninergic system. 15. the application of the mixed crystal of agomelatine as described in any one in claim 1-3 in the preparation medicine, described medicine is used for the treatment of sleep disorder, tension, anxiety disorder, seasonal affective disorder, heart disease. Blood vessel disease, digestive system disease, schizophrenia, phobias, or depression. 16. The use of the mixed crystal of agomelatine according to any one of claims 1-3 in the preparation of medicines for treating severe depression or insomnia or fatigue caused by jet lag.